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EP0237366A1 - Aminoalkohole, deren Herstellungsverfahren und deren Verwendungen namentlich in der Therapie - Google Patents

Aminoalkohole, deren Herstellungsverfahren und deren Verwendungen namentlich in der Therapie Download PDF

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Publication number
EP0237366A1
EP0237366A1 EP87400116A EP87400116A EP0237366A1 EP 0237366 A1 EP0237366 A1 EP 0237366A1 EP 87400116 A EP87400116 A EP 87400116A EP 87400116 A EP87400116 A EP 87400116A EP 0237366 A1 EP0237366 A1 EP 0237366A1
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EP
European Patent Office
Prior art keywords
methyl
salts
dichlorophenyl
propanol
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP87400116A
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English (en)
French (fr)
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EP0237366B1 (de
Inventor
Gilbert Aubard
Jacques Bure
Alain Pierre Calvet
Claude Gouret
Agnès Geneviève Grouhel
Jean-Louis Junien
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Jouveinal SA
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Jouveinal SA
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Publication date
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Priority to AT87400116T priority Critical patent/ATE42540T1/de
Publication of EP0237366A1 publication Critical patent/EP0237366A1/de
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Publication of EP0237366B1 publication Critical patent/EP0237366B1/de
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/092—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to new amino alcohols derived from 2- (3,4-dichlorobenzyl) -2-aminoethanol, their preparation process and their applications, in particular in therapy.
  • the alkyl and lower alkanoyl radicals are linear or branched and contain from 1 to 5 carbon atoms; the alkenyl radical preferably has from 2 to 5 carbon atoms and, in particular, 3 carbon atoms, while the cycloalkyl radicals preferably have from 3 to 6 carbon atoms.
  • acids in particular those which are therapeutically acceptable, which form addition salts with the compounds according to the invention, mention may be made, by way of example, of mineral or organic acids, such as acetic, benzenesulfonic, camphorsulfonic acids. , citric, ethanesulfonic, fumaric, hydrobromic, hydrochloric, lactic, maleic, malic, methanesulfonic, nitric, pamoic, phosphoric, salicylic, stearic, succinic, sulfuric, tartaric.
  • mineral or organic acids such as acetic, benzenesulfonic, camphorsulfonic acids.
  • the invention relates to both the racemic forms and the optically active forms of the precisely defined compounds of formula (I).
  • the compounds according to the invention exhibit activities on the central nervous system (CNS) as well as analgesic properties which are unexpected in amino alcohols.
  • the invention therefore relates to the use of the compounds (I) as an analgesic medicament and acting on the central nervous system.
  • R 1 is methyl
  • R 2 is hydrogen
  • R 3 is hydrogen or methyl
  • the compounds of formulas II and IV can be prepared by various methods, including that described in examples 1 and 2 of French patent No. 77 0236 0 , which consists firstly in condensing 3,4-dichlorobenzyl chloride or bromide with isocyano-esters of formula III in which R1 is a lower alkyl radical such as as previously defined and A a low molecular weight alkyl radical to obtain, according to Example 1 of the patent, racemic amino acids of formula II.
  • Example 2 of this same patent makes it possible to obtain, on the one hand, the products of formula IV in racemic and optically active forms and, on the other hand, the amino acids of formula II in optically active forms.
  • the reduction reactions consist in reducing the carbonyl groups of the carboxylic functions and / or the amide functions in order to obtain primary alcohol functions and / or secondary amine functions respectively.
  • the reductions are carried out in non-dissociating aprotic media in solvents such as diethyl ether, diisopropyl ether, 1,2-dimethoxyethane or else tetrahydrofuran (THF) which is the preferred solvent.
  • solvents such as diethyl ether, diisopropyl ether, 1,2-dimethoxyethane or else tetrahydrofuran (THF) which is the preferred solvent.
  • the BMS complex is used in stoichiometric excess relative to the products to be reduced in order to obtain a complete reaction. This excess is different depending on the nature of the structures involved and depends on the one hand on the number of carbonyl groups to be reduced and on the other hand on the presence in these structures of other groups or functions reacting with BMS. Thus, depending on the case, 2 to 8 moles of BMS are used per mole of product to be treated, the preferred amounts however being 2.5 to 3.5 moles of BMS per mole of compound Ic (reaction of) and from 4 to 6 moles per mole of compounds II and IV (reactions a and d ").
  • the products subjected to the reduction reactions namely 1 to 10 parts by weight are introduced in the absence of moisture and under a nitrogen atmosphere in 100 parts by volume of THF and more particularly from 3 to 7 parts in 100.
  • the quantity of BMS previously defined as appropriate is introduced and then the mixture is heated under reflux to have a total reaction, a duration which can be between 30 minutes and 10 hours, however a duration of 3 to 5 hours is the most favorable.
  • the amino alcohol is then released from its complex with the reducing agent by the addition of methanol and then sodium hydroxide and finally isolated by conventional methods described in the examples presented.
  • the mono and dialkylation reactions are carried out either by the action of an alkyl halide or by the action of an aldehyde and formic acid called reductive alkylation.
  • the solvents used are inert with respect to alkyl halides such as, for example, toluene and acetonitrile.
  • alkyl halides such as, for example, toluene and acetonitrile.
  • a base is added which can be mineral, such as anhydrous sodium carbonate, or organic, such as triethylamine, to promote the reaction.
  • the temperature and reaction time conditions are adapted to the nature of the solvent and to the reactivity of the products and can be between 20 and 110 ° C. for 1 to 24 hours. Suitable temperatures and times are 40 to 110 ° C for 2 to 5 hours, the alkylated products being then separated and purified by usual methods described in the examples.
  • reactions e and e ' the reactions consist in first reacting the aldehydes R 4 -CHO previously defined with the product to be alkylated, then in subjecting the non-isolated intermediate compounds to a reduction with pure formic acid, the first part of the reaction being conducted at a temperature between 20 and 50 ° C, the second between 0 6 and 100 ° C and for one to five hours.
  • acylation reactions (c) defined above are carried out either in an anhydrous monophasic medium such as toluene and in the presence of an organic base such as triethylamine, or in two-phase medium as in a water-1,2-dichloroethane mixture in the presence of 'sodium hydroxide. In both cases, the acid chloride is used in stoichiometric ratio or in default with respect to the amino alcohol involved.
  • the mineral or organic base is introduced cold, then the acid chloride in an amount of 0.5 to 1 mole.
  • the reaction is carried out by stirring the mixture for 1 to 5 hours at a temperature between 0 and 30 ° C and preferably from 1 to 2 hours, at a temperature between 10 and 20 ° C, before treating it to isolate the product.
  • the melting points are determined by the capillary tube method with a "Mettler FP1" device and are not corrected,
  • the determination of the rotary powers is carried out in tubes of 2 dm in length.
  • the solution obtained is extracted with twice 150 ml of ether.
  • the alkaline mixture is extracted with 3 times 200 ml of ether, the ethereal phases combined washed with a saturated solution of sodium chloride and then dried.
  • the amino alcohol is obtained in the form of a solid, white and amorphous residue.
  • the levorotatory amino alcohol is obtained by reduction of 60.0 g (242 mmol) of (-) 2- (3,4-dichlorobenzyl) alanine.
  • the crude product is purified by crystallization from an ether-hexane mixture.
  • the product After evaporation of the extraction solvent, the product is obtained in the form of an amorphous white solid.
  • the product is filtered, washed with ice water until the washings are neutral, then dried at 80 ° C under vacuum to constant weight.
  • the insoluble material is filtered and eliminated, the residue obtained after concentration of the filtrate is dissolved in 350 ml of normal hydrochloric acid.
  • the solution is extracted 3 times with 125 ml of ether and then basified to pH 12 with a concentrated sodium hydroxide solution saturated with sodium chloride.
  • the alkaline mixture is extracted 3 times with 200 ml of methylene chloride.
  • the combined organic phases are treated in the usual way and after evaporation the product is obtained in the form of a white, amorphous solid.
  • the product is prepared according to Example 4 - stage 1 from 50.0 g (0.164 mol) of (+) 2-pentyl-2- (3,4 dichlorobenzyl) glycine.
  • the product is obtained by reduction of 47.4 g (0.143 mol) of the derivative obtained in preceding stage 1.
  • the insoluble material is filtered and suspended in 2 l of demineralized water, alkanized with sodium hydroxide solution and the mixture is extracted 3 times with 750 ml of ether.
  • the phases ethereal together are treated in the usual way.
  • the 13.8 g residue is crystallized from 1 l of hexane.
  • the product is filtered and then dried under vacuum.
  • the product is obtained in the form of a yellow and viscous oil.
  • R 1 CH 3 ;
  • R 2 H ;
  • the residue obtained by concentrating the filtrate is taken up in 100 ml of 2N hydrochloric acid.
  • the acid suspension is extracted twice with 50 ml of ether, then basified to pH 12 with sodium hydroxide solution and again extracted with ether.
  • the ethereal phases are combined and processed in the usual way. After evaporation, the amino alcohol is obtained in the form of a viscous oil.
  • R 3 -CO-C (CH 3 ) 3 .
  • Example 8A The product is prepared according to the procedure described in Example 8A by reaction between 2.2 g (14.2 mmol) of phenylacetic acid chloride and 5.0 g (21.3 mmol) of amino alcohol obtained at Example 1A (OJ 1275).
  • R 1 C H 3 ;
  • R 2 H;
  • R 3 -CH 2 -CH 2 -C 6 H 5
  • the acid phase is made alkaline with a concentrated solution of sodium hydroxide and then extracted 3 times with 75 ml of ether.
  • the ethereal phases are treated in the usual way and the oily residue obtained after evaporation of the ether is crystallized from 150 ml of hexane.
  • the white crystallized product is filtered and dried.
  • R 1 C H 3 ;
  • R 2 CH 3 ;
  • R 3 CH 2 -CH 2 -C 6 H 5
  • the product is prepared according to the procedure described in the previous example, from 8.9 g (26.3 mmol) of the aminoalcohol prepared in Example 10B (J O 1456).
  • the product is in the form of a viscous oil.
  • R 1 (CH 3 );
  • the product is prepared according to the procedure of Example 11 above from 3.8 g (13.8 mmol) of the amino alcohol obtained in Example 7.
  • the product is obtained in the form of a yellow oil pale, viscous.
  • Examples 14A, 14B and 14C are respectively obtained from the amino alcohols of Examples 1A (OJ 1275), 1B (OJ 1307) and 1C by reaction with formaldehyde and formic acid. The same is true for the products of Examples 15 and 16 which are respectively prepared from the amino alcohols of Examples 2 and 3.
  • the solution is acidified to pH 1 with concentrated hydrochloric acid and extracted three times with 50 ml of ether.
  • the ethereal phases are discarded and the acid phase basified to pH 12 with a concentrated solution of sodium hydroxide, then extracted again with 3 times 75 ml of ether.
  • R 1 CH 3 ; NR 2 .
  • R 3 piperidyl.
  • the solution is brought to reflux with stirring for one hour and then cooled to room temperature; 4.58 g (43.2 mmol) of sodium carbonate are then added and the suspension obtained is brought to reflux again for 20 hours.
  • the filtrate is removed, the insoluble material is taken up in 500 ml of water.
  • the suspension obtained is made alkaline until p H 12 by addition of ION sodium hydroxide solution.
  • the mixture is extracted 3 times with 250 ml of ether.
  • the combined ethereal phases are processed in the usual way. After evaporation, the product is obtained in the form of a white, amorphous solid.
  • the suspension is stirred at 100 ° C for 48 hours.
  • the insoluble material is filtered and the dimethylformamide removed by vacuum distillation.
  • the combined hydrochloric phases are made alkaline by adding sodium hydroxide solution to pH 12. The mixture is then extracted with ether. The combined ethereal phases are washed with a saturated sodium chloride solution and then dried over Na 2 SO 4 . The ether is removed by distillation.
  • the product is obtained according to the procedure of example 18 above, from 46.8 g (0.200 mol) of the amino alcohol of example 1A, from 42.2 g (0.220 mol) of N hydrochloride -methyl bis (2-chloroethyl) amine and 54 g (0.640 mol) of sodium bicarbonate.
  • the pharmacological study of the products of the invention shows interesting properties, in particular an activity on the central nervous system ( S .NC) accompanied by analgesic properties. Furthermore, their toxicity has been determined. All of these studies are reported in the following section and. the results obtained demonstrate the therapeutic activity of these products, as well as their usefulness as drugs.
  • Acute toxicity has been studied orally in male mice.
  • the products were administered in aqueous solution at a rate of 2 ml / 100 g.
  • the animals were then observed for three hours after administration and then daily for fourteen days, at which time they were sacrificed and autopsied.
  • the LD50 (lethal doses causing the death of 50% of the animals) were calculated according to the method of Reed JL and Muench H. (Am. J. Hyg. 1939, 27, 493). Their value is generally between 750 and 12 0 0 mg-kg -1 and sometimes higher than this last figure.
  • mice This activity was sought in mice by the tail suspension test according to the technique described by Thierry et al. (Behavioral and Neural Biology, 1984, 41, 180-189), test which has was proposed as a model in animals, to select products active on the CNS
  • the tests were carried out on batches of 10 male mice for each product and at each dose, the substances to be studied being administered in aqueous solution, orally, one hour before the test, a control batch of animals not receiving than distilled water.
  • the results of the tests are expressed as percentages of activity relative to the batch of control animals.
  • the animals are fasted with food and drink. They then receive orally and in aqueous solution the products to be studied in an amount of 2 ml of solution per 10 0 g of body weight, then 30 minutes after an intraperitoneal injection of 0.25 ml of an acetic acid solution to 0.25% (w / v) maintained at 37 ° C.
  • the animals are considered to be analgesized, when they have a number of cramps less than half the average of cramps presented by the animals of the control batch.
  • the products were administered at a dose of 30 mg-kg and the results are presented in percentages of analgesized animals. For certain products, several doses were administered and the calculation of their ED 50 (dose causing analgesia of 50 % of animals) was determined in log probit.
  • the products of the invention have an activity on the central nervous system at doses of 32 and 128 mg-kg greater than that of clomipramine.
  • analgesic properties of the products of the invention are clearly demonstrated at a dose of 30 mg-kg 1 by the oral route.
  • the calculation of ED 50 shows a superiority of activity compared to Noramidopyrine, a known analgesic, taken as a reference substance.
  • the products of the invention therefore show both psychotropic and analgesic properties, which are of multiple clinical utility in the form of medicaments intended for human or veterinary therapy.
  • These preparations are, inter alia, particularly intended for the treatment of psychopathological and neuropathological disorders, as well as pain syndromes of various etiologies.
  • compositions are administered in the form of compositions by routes suitable for the nature and severity of the condition to be treated, and this in forms compatible with the routes of treatment. administration envisaged.
  • the relatively low toxicity of the products authorizes a daily dosage in humans, close to one gram of product. More usually this dosage is between 0.010 and 0.500 grams of the product per day, this amount can be divided into several doses.
  • compositions according to the invention comprise from 1 to 40% by weight of active principle consisting of one or more compounds of formula (I) or their salts and 99 to 60% by weight of a pharmaceutical vehicle compatible with the physical form of the proposed composition.
  • compositions are prepared by methods known per se and their form is compatible with the route of administration. Examples are tablets, dragees, capsules, powders, injectable or drinkable solutions, suspensions, gels and suppositories. Their manufacture is illustrated in a nonlimiting manner by the description of the methods of preparation of the tablets and isotonic solutions injectable with the active principles of the invention.
  • the isotonic solute is divided into ampoules of appropriate volume which are, after sealing, sterilized by thermal means known per se, or else the solute is sterilized by filtration, divided into ampoules which are then sealed, all operations being carried out under sterile atmosphere.

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  • Engineering & Computer Science (AREA)
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  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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EP87400116A 1986-01-30 1987-01-19 Aminoalkohole, deren Herstellungsverfahren und deren Verwendungen namentlich in der Therapie Expired EP0237366B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT87400116T ATE42540T1 (de) 1986-01-30 1987-01-19 Aminoalkohole, deren herstellungsverfahren und deren verwendungen namentlich in der therapie.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR8601295 1986-01-30
FR8601295A FR2593499B1 (fr) 1986-01-30 1986-01-30 Aminoalcools, leur procede de preparation et leurs applications, notamment en therapeutique

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EP0237366A1 true EP0237366A1 (de) 1987-09-16
EP0237366B1 EP0237366B1 (de) 1989-04-26

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EP87400116A Expired EP0237366B1 (de) 1986-01-30 1987-01-19 Aminoalkohole, deren Herstellungsverfahren und deren Verwendungen namentlich in der Therapie

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US (1) US4994617A (de)
EP (1) EP0237366B1 (de)
JP (1) JPH089580B2 (de)
KR (1) KR950006891B1 (de)
AT (1) ATE42540T1 (de)
AU (1) AU590664B2 (de)
BR (1) BR1100977A (de)
CA (1) CA1294961C (de)
DE (1) DE3760117D1 (de)
DK (1) DK169538B1 (de)
ES (1) ES2008109B3 (de)
FI (1) FI87068C (de)
FR (1) FR2593499B1 (de)
GR (1) GR3000026T3 (de)
IE (1) IE59448B1 (de)
NZ (1) NZ218988A (de)
PT (1) PT84223B (de)

Cited By (3)

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Publication number Priority date Publication date Assignee Title
EP0569276A1 (de) * 1992-05-05 1993-11-10 Institut De Recherche Jouveinal (I.R.J) Neue Verwendung von (S) Amino-2-dichloro-3,4-benzyl)-2-propanol-1 Enantiomere Derivate
FR2761686A1 (fr) * 1997-04-07 1998-10-09 Sipsy Sa Nouveau procede de preparation du (+/-)3-(3,4- dichlorophenyl)-2-dimethylamino-2-methyl-propan-1-ol ou cericlamine (inn)
WO2005060968A1 (en) 2003-12-11 2005-07-07 Sepracor Inc. Combination of a sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression

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US4939133A (en) * 1985-10-01 1990-07-03 Warner-Lambert Company N-substituted-2-hydroxy-α-oxo-benzeneacetamides and pharmaceutical compositions having activity as modulators of the arachidonic acid cascade
US5482947A (en) * 1990-11-19 1996-01-09 Talley; John J. Retroviral protease inhibitors
US5472970A (en) * 1992-05-05 1995-12-05 Institut De Recherche Jouveinal S.A. Allylaminoesters and their application in therapeutics
FR2690917B1 (fr) * 1992-05-05 1994-06-17 Jouveinal Inst Rech Aminoesters, leur procede de preparation et leur application en therapeutique.
US5367094A (en) * 1993-06-04 1994-11-22 Yukong, Ltd. Convenient process for the preparation of chiral or racemic phenylalaninols and their N-blocked derivatives
US7216702B2 (en) * 2003-02-28 2007-05-15 Yates Petroleum Corporation Methods of evaluating undersaturated coalbed methane reservoirs
US7467260B2 (en) * 2004-10-08 2008-12-16 International Business Machines Corporation Method and apparatus to purge remote node cache lines to support hot node replace in a computing system
CZ2009385A3 (cs) * 2009-06-16 2010-07-28 Zentiva, K. S. Zpusob výroby (S)-4-methylamino-3-(3,4-dichlorfenyl)butan-1-olu

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0569276A1 (de) * 1992-05-05 1993-11-10 Institut De Recherche Jouveinal (I.R.J) Neue Verwendung von (S) Amino-2-dichloro-3,4-benzyl)-2-propanol-1 Enantiomere Derivate
FR2690916A1 (fr) * 1992-05-05 1993-11-12 Jouveinal Inst Rech Nouveaux énantiomères dérivés du (S)-amino-2-(dichloro-3,4-benzyl)-2-propanol-1.
AU665821B2 (en) * 1992-05-05 1996-01-18 Institut De Recherche Jouveinal (I.R.J.) New enantiomers derived from (S)-2-amino-2-(3,4-dichlorobenzyl)-1-propanol
FR2761686A1 (fr) * 1997-04-07 1998-10-09 Sipsy Sa Nouveau procede de preparation du (+/-)3-(3,4- dichlorophenyl)-2-dimethylamino-2-methyl-propan-1-ol ou cericlamine (inn)
WO1998045248A1 (en) * 1997-04-07 1998-10-15 Jouveinal Novel process for the preparation of (+/-)3- (3,4-dichlorophenyl)-2- dimethylamino-2-methylpropan-1-ol or cericlamine (inn)
US6121491A (en) * 1997-04-07 2000-09-19 Warner-Lambert Company Process for the preparation of (+/-)3-(3,4-dichlorophenyl)-2-dimethylamino-2-methylpropan-1-OL or cericlamine (INN)
WO2005060968A1 (en) 2003-12-11 2005-07-07 Sepracor Inc. Combination of a sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression
EP2343073A2 (de) 2003-12-11 2011-07-13 Sepracor Inc. Kombination eines Beruhigungsmittels und eines Neurotransmittermodulators und Verfahren zur Verbesserung der Schlafqualität und Behandlung von Depressionen

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DK169538B1 (da) 1994-11-28
FI87068B (fi) 1992-08-14
US4994617A (en) 1991-02-19
BR1100977A (pt) 1999-10-13
IE870062L (en) 1987-07-30
FI870418A0 (fi) 1987-01-30
CA1294961C (en) 1992-01-28
FI870418L (fi) 1987-07-31
JPH089580B2 (ja) 1996-01-31
FI87068C (fi) 1992-11-25
IE59448B1 (en) 1994-02-23
FR2593499B1 (fr) 1988-08-12
DK40687D0 (da) 1987-01-26
EP0237366B1 (de) 1989-04-26
AU590664B2 (en) 1989-11-09
KR950006891B1 (ko) 1995-06-26
ATE42540T1 (de) 1989-05-15
GR3000026T3 (en) 1990-01-19
KR870007101A (ko) 1987-08-14
PT84223B (pt) 1989-05-31
PT84223A (fr) 1987-02-01
DK40687A (da) 1987-07-31
AU6795987A (en) 1987-08-06
JPS62190150A (ja) 1987-08-20
NZ218988A (en) 1990-02-26
FR2593499A1 (fr) 1987-07-31
DE3760117D1 (en) 1989-06-01
ES2008109B3 (es) 1989-07-16

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